This application titled "Small Molecule Neurotrophin Mimetics to Treat Huntington's Disease" is in response to NINDS Exploratory/Developmental Projects in Translational Research (R21;program announcement: PAR- 08-232). The current proposal will test whether small molecule agonists for the TrkB neurotrophin receptor will be effective treatments for neurodegeneration associated with Huntington's Disease (HD). The TrkB receptor binds brain derived neurotrophic factor (BDNF), which is a growth factor that is critically involved in neuronal survival and synapse function. Reduced levels of BDNF contribute importantly to pathology in numerous neurodegenerative disorders, including Alzheimer's, Parkinson's and Huntington's (HD). Given the pervasive neuroprotective role of BDNF/TrkB, the demand for small molecule TrkB ligands that lack undesired side- effects is large and long standing. Such compounds have been developed for the first time by the applicant and his colleague. These novel TrkB agonists mimic many of BDNF's effects on TrkB signaling and cell survival in in vitro and in vivo studies. Thus, they are ready to be tested for their effects on preventing pathology in neurodegenerative disease. This proposal will focus on HD since the loss of BDNF in HD brains is a fundamental contributor to the neuropathologies associated with the disorder. HD is a fatal neurodegenerative disease characterized by progressive motor, psychological, and cognitive deficits that emerge in adulthood. It is caused by a mutation in the gene that encodes the huntingtin protein. The proposed studies will use a transgenic mouse model of HD to execute two aims: (i) determine if 2 different BDNF mimetics will slow the emergence of, or prevent, motor, memory and psychiatric deficits associated with HD using a battery of behavioral tests;and (ii) test whether BDNF mimetics ameliorate HD-related neuropathology. Positive results in these studies will identify a novel and feasible therapeutic strategy for reducing numerous HD phenotypes (motor, psychological and cognitive impairments as well as neuropathology), which are currently untreatable, as well as other age-related neurodegenerative diseases. The current R21 proposal is designed to provide proof-of-concept and target validation data that will support a subsequent U01 application to determine the effectiveness of these novel small molecule TrkB ligands against neurodegeneration. PUBLIC HEALTH RELEVANCE: The current proposal will test the efficacy of novel, small molecule agonists for the TrkB neurotrophin receptor to treat neurodegenerative disease, specifically Huntington's Disease (HD). The TrkB receptor binds brain derived neurotrophic factor (BDNF), the loss of which in HD brains is a fundamental contributor to the neuropathologies associated with the disorder. Thus, these first-in-class TrkB agonists are likely candidates to prevent neurodegeneration associated with a disease that currently has no cure and success in the proposed HD studies will point to TrkB agonist applications in other CNS disorders including Alzheimer's disease and depression.